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A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

Need, AC; Ge, DL; Weale, ME; Maia, J; Feng, S; Heinzen, EL; Shianna, KV; ... Goldstein, DB; + view all (2009) A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia. PLOS GENET , 5 (2) , Article e1000373. 10.1371/journal.pgen.1000373. Green open access

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Abstract

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (> 100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

Type: Article
Title: A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1000373
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1000373
Language: English
Additional information: © 2009 Need et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The US patients were part of an NIMH-funded Clinical Research Center at Case Western Reserve University and prospective clinical trials at Vanderbilt University. The Aberdeen, Munich, Italian replication cohort and US cohort genotyping and the Genetics of Memory/ Genetics of Epilepsy cohort was funded by Duke Institute for Genome Sciences and Policy start-up funding provided to DBG. Recruitment of the patients from Munich was partially supported by GlaxoSmithKline (GSK). DBG is a paid consultant for GSK. Other than these GSK contributions, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: RARE STRUCTURAL VARIANTS, PSYCHIATRIC GENETICS, CANDIDATE GENES, COMMON VARIANT, ASSOCIATION, RISK, POPULATION, LINKAGE, METAANALYSIS, PROBABILITY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/143159
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